Real-world effects of tezacaftor/ivacaftor (TEZ/IVA) in people with cystic fibrosis (pwCF): interim results of a long-term safety study using US CF Foundation Patient Registry (CFFPR) data

Purpose of review Highly effective modulators of cystic fibrosis transmembrane conductance regulator (CFTR) function have had dramatic impact on pulmonary and nutritional outcomes in persons with cystic fibrosis (pwCF). The impact on liver disease in pwCF was not the focus of the registration trials. The purpose of this review is to assess the current literature on the impact of HEMT on liver disease, progression, regression, and safety. Recent findings Short-term studies of HEMT in pwCF have shown that there is no significant impact on the frequency of liver enzyme abnormalities. There is no evidence for significant improvement in liver enzymes over time on HEMT therapy. There is conflicting data on improvement in liver fibrosis determined by fibrosis indices (APRI and GPR) or elastography. One study showed improvement, and another showed worsening in younger (<20 years old) pwCF. There are reports of resolution or improvement in hepatic steatosis. There are rare reports of severe acute hepatitis and one report of hepatic decompensation leading to liver transplantation due to drug-induced liver disease. Summary HEMT have not been shown to have a significant impact on improving liver disease or preventing fibrosis with short-term therapy. Longer studies are needed to assess the impact of HEMT on liver disease in pwCF.

Section: Impact Of Highly Effective Cftr Modulator Therapies On Bioma...mentioning

confidence: 82%

Cystic fibrosis liver disease in the post-modulator era

Narkewicz

2023

“…The possibility of ETI being inconsistently and/or less beneficial to pwCF over time has also been raised as a reason for clinicians to approach treatment discontinuation cautiously [53]. Data from open-label extension [54] and registry [55] studies suggest that the clinical benefits of ETI should be sustained, but it is reasonable to expect that individual results will vary. This point underscores the importance of shared decision-making [56].…”

Section: Clinical Trials Evaluating Treatment Simplification In Peopl...mentioning

confidence: 99%

Chronic daily respiratory care needs in people with cystic fibrosis treated with highly effective cystic fibrosis transmembrane conductance regulator modulators

Wajda,

Roesch,

Gifford

2023

Purpose of review Cystic fibrosis is a genetic disease that increases risk of death from respiratory failure because of impairment in mucociliary clearance. Complex daily care regimens including medications and airway clearance techniques (ACTs) aim to preserve lung function and alleviate symptoms for people with cystic fibrosis (pwCF). The success of highly effective modulator therapy (HEMT) permits evaluation of treatment simplification. In this review, we evaluate adjustments made in daily respiratory care among pwCF taking HEMT and the feasibility of treatment simplification. Recent findings Treatment simplification has been identified as a top priority among pwCF, with recent studies showing pwCF are willing to sacrifice mild to moderate amounts of lung function and longevity to reduce treatment burden. Retrospective studies have shown that patients taking HEMT with better baseline lung function have lower adherence to and prescription of inhaled medications. A randomized, controlled trial found that short-term discontinuation of dornase alfa or hypertonic saline was clinically noninferior to continuation of these medications. Major knowledge gaps remain about withdrawing ACTs. Summary This review highlights trials evaluating the feasibility of treatment simplification among pwCF taking HEMT. More data is needed to evaluate approaches to simplification in this phenotypically diverse patient population.

“…The occurrence and frequency of PEx have sharply declined since the approval of elexacaftor/tezacaftor/ivacaftor (ETI) in the US in 2019 [69]. In a study utilizing the CF Foundation registry, just 11–12% of pwCF on ETI had at least one PEx per year requiring IV antibiotics at home or in hospital post-ETI compared to a stable prevalence of 40–43% in the 5 years leading up to ETI approval [8 ▪ ]. Part of this decrease is likely attributable to the reduced frequency of viral respiratory tract infections, a common trigger of PEx, as the post-ETI period for this study coincided with social distancing practices during the COVID pandemic.…”

Section: Shifting Epidemiology Of Pulmonary Exacerbationsmentioning

confidence: 99%

“…They also have a significant adverse impact on work/school productivity, caregiver burden [6], and costs to the healthcare system [7]. The epidemiology of PEx in CF is evolving with more widespread use of highly effective modulators, which dramatically reduce the frequency of these events [8 ▪ ]. As the clinical presentation of PEx can be more subtle in the era of highly-effective CFTR modulator therapy, these events can be overlooked by pwCF and their healthcare providers, underscoring the need to identify better tools and approaches to enhance their detection.…”

Section: Introductionmentioning

confidence: 99%

Breath of fresh insight: unraveling the evolution of our understanding of cystic fibrosis pulmonary exacerbations

Somayaji,

Quon

2023

Purpose of review Pulmonary exacerbations are critical events with significant negative impacts in persons with cystic fibrosis, but their diagnosis and management are highly variable. Highly effective modulator therapies have greatly improved health and reduced exacerbation events, but have also reshaped how they present. This review discusses the complexities of the diagnosis and management of pulmonary exacerbations as well as the emerging work and evidence in this area. Recent findings The shifting epidemiology and our understanding of risk factors for pulmonary exacerbations are discussed. As symptoms may be more subtle in the modulator context, novel technologies including studies of remote monitoring are presented. The continued relevance of pulmonary exacerbations, the heterogeneity in their management, as well as current and forthcoming clinical trials to optimize treatment approaches are detailed. Summary In spite of the dramatic reductions in pulmonary exacerbations, airway infections persist, a proportion of persons with cystic fibrosis either on or off modulator therapies continue to experience exacerbation events, and long-term data is lacking. Innovative approaches and studies will be crucial to enable standardized and generalizable strategies to improve outcomes in persons with cystic fibrosis.